The present invention is directed to compositions (i.e. drug delivery systems) and methods for treating ocular conditions, and for preventing the occurrence of certain ocular conditions. In particular the present invention is directed to pharmaceutical compositions and methods for treating and for preventing posterior ocular conditions, for example by preventing retinal, choroidal and/or macular neovascularizations and/or for treating various types of macular degeneration (such as age related macular degeneration), by use of a drug delivery system comprising an anti-neovascular agent.
In the industrialized world the average life expectancy is over 80 years of age and is increasing steadily. Unfortunately, the quality of life for the elderly is often dramatically decreased by the ocular condition known as age related macular degeneration (“ARMD” or “AMD”). AMD is the leading cause of blindness worldwide and the World Health Organization has estimated that about 14 million people are blind or severely impaired because of AMD. The affliction of AMD has great impact on the physical and mental health of the geriatric population and their families and presents a significant public health care burden. The seminal characteristic of AMD is progressive loss of central vision attributable to degenerative and neovascular changes in the macula, a specialized area in the center of the retina.
There are two forms of AMD, atrophic or dry AMD and neovascular or wet AMD. Typically AMD begins as dry AMD. Dry AMD is characterized by the formation of yellow plaque like deposits called drusen in the macula, between the retinal pigment epithelium (RPE) and the underlying choroid. About 15% of dry AMD patients develop wet AMD which is characterized by choroidal neovascularization, that is by the formation of new blood vessels in the choroid, and vision loss.
While there is no cure for AMD there are known treatments for wet AMD (the less prevalent form of AMD), such as use of anti-neovascular agents and photodynamic therapy (laser irradiation of the macular). Anti-neovascular agents for treatment of wet AMD include agents which block the action of vascular endothelial growth factor (VEGF) thereby slowing angiogenesis (formation of new blood vessels in the retina) which leads to choroidal neovascularization and loss of vision in wet AMD patients. Such “anti-VEGF” agents approved or in clinical study for treating wet AMD include bevacizumab (Avastin), ranibizumab (Lucentis), and pegaptanib (Macugen). Bevacizumab is a full-length anti-VEGF antibody approved for use in metastatic colon cancer. Ranibizumab is a humanized anti-VEGF monoclonal antibody fragment that inhibits all isotypes of VEGF and pegaptanib is a VEGF-neutralizing aptamer that specifically inhibits one isoform of VEGF (VEGF-165).
Other known anti-VEGF agents include small interfering RNA (siRNAs); corticosteroids such as anacortave acetate, triamcinolone acetonide and fluocinolone acetonide; receptor tyrosine kinase inhibitors (such as vatalanib and Ruboxistaurin [decreases protein kinase C activity]); squalamine lactate, and; growth factors, including pigment epithelium-derived factor. siRNAs can inhibit VEGF production and VEGF receptor production, corticosteroids can treat the DME aspect of wet AMD, receptor tyrosine kinase inhibitors inhibit downstream effects of VEGF, and squalamine lactate inhibits plasma membrane ion channels with downstream effects on VEGF.
An ocular condition can include a disease, aliment or condition which affects or involves the eye or one of the parts or regions of the eye. Broadly speaking the eye 30 includes the eyeball and the tissues and fluids which constitute the eyeball, the periocular muscles (such as the oblique and rectus muscles) and the portion of the optic nerve which is within or adjacent to the eyeball. A front of the eye or anterior ocular condition is a disease, ailment or condition which affects or which involves an ocular region or site, such as a periocular muscle, an eye lid or an eye ball tissue or fluid which is located anterior to the posterior wall of the lens capsule or ciliary muscles. Thus, a front of the eye ocular condition primarily affects or involves, the conjunctiva, the cornea, the conjunctiva, the anterior chamber, the iris, the posterior chamber (behind the iris but in front of the posterior wall of the lens capsule), the lens and the lens capsule as well as blood vessels, lymphatics and nerves which vascularize, maintain or innervate an anterior ocular region or site.
A front of the eye (anterior) ocular condition can include a disease, ailment or condition, such as for example, aphakia; pseudophakia; astigmatism; blepharospasm; cataract; conjunctival diseases; conjunctivitis; corneal diseases; corneal ulcer; dry eye syndromes; eyelid diseases; lacrimal apparatus diseases; lacrimal duct obstruction; myopia; presbyopia; pupil disorders; refractive disorders and strabismus. Glaucoma can be considered to be a front of the eye ocular condition because a clinical goal of glaucoma treatment can be to reduce a hypertension of aqueous fluid in the anterior chamber of the eye (i.e. Reduce intraocular pressure).
A posterior (or back of the eye) ocular condition is a disease, ailment or condition which primarily affects or involves a posterior ocular region or site such as choroid or sclera (in a position posterior to a plane through the posterior wall of the lens capsule), vitreous, vitreous chamber, retina, optic nerve (i.e. the optic disc), and blood vessels and nerves which vascularize or innervate a posterior ocular region or site.
Thus, a posterior ocular condition can include a disease, ailment or condition, such as for example, macular degeneration (such as non-exudative age related macular degeneration and exudative age related macular degeneration); choroidal neovascularization; acute macular neuroretinopathy; macular edema (such as cystoid macular edema and diabetic macular edema); Behcet's disease, retinal disorders, diabetic retinopathy (including proliferative diabetic retinopathy); retinal arterial occlusive disease; central retinal vein occlusion; uveitic retinal disease; retinal detachment; ocular trauma which affects a posterior ocular site or location; a posterior ocular condition caused by or influenced by an ocular laser treatment; posterior ocular conditions caused by or influenced by a photodynamic therapy; photocoagulation; radiation retinopathy; epiretinal membrane disorders; branch retinal vein occlusion; anterior ischemic optic neuropathy; non-retinopathy diabetic retinal dysfunction, retinitis pigmentosa and glaucoma. Glaucoma can also be considered a posterior ocular condition because a therapeutic goal of glaucoma treatment is to prevent the loss of or reduce the occurrence of loss of vision due to damage to or loss of retinal cells or optic nerve cells (i.e. neuroprotection).
As stated macular degeneration, such as AMD is a leading cause of blindness in the world and it is estimated that thirteen million Americans have evidence of macular degeneration. Macular degeneration results in a break down the macula, the light-sensitive part of the retina responsible for the sharp, direct vision needed to read or drive. Central vision is especially affected. Macular degeneration is diagnosed as either dry (atrophic) or wet (exudative). The dry form of macular degeneration is more common than the wet form of macular degeneration, with about 90% of AMD patients being diagnosed with dry AMD. The wet form of the disease usually leads to more serious vision loss. Macular degeneration can produce a slow or sudden painless loss of vision. The cause of macular degeneration is not clear. The dry form of AMD may result from the aging and thinning of macular tissues, depositing of pigment in the macula, or a combination of the two processes. With wet AMD, new blood vessels grow beneath the retina and leak blood and fluid. This leakage causes retinal cells to die and creates blind spots in central vision.
Macular edema (“ME”) can result in a swelling of the macula. The edema is caused by fluid leaking from retinal blood vessels. Blood leaks out of the weak vessel walls into a very small area of the macula which is rich in cones, the nerve endings that detect color and from which daytime vision depends. Blurring then occurs in the middle or just to the side of the central visual field. Visual loss can progress over a period of months. Retinal blood vessel obstruction, eye inflammation, and age-related macular degeneration have all been associated with macular edema. The macula may also be affected by swelling following cataract extraction. Symptoms of ME include blurred central vision, distorted vision, vision tinted pink and light sensitivity. Causes of ME can include retinal vein occlusion, macular degeneration, diabetic macular leakage, eye inflammation, idiopathic central serous chorioretinopathy, anterior or posterior uveitis, pars planitis, retinitis pigmentosa, radiation retinopathy, posterior vitreous detachment, epiretinal membrane formation, idiopathic juxtafoveal retinal telangiectasia, Nd:YAG capsulotomy or iridotomy. Some patients with ME may have a history of use of topical epinephrine or prostaglandin analogs for glaucoma. The first line of treatment for ME is typically anti-inflammatory drops topically applied. The increase in retinal capillary permeability and subsequent retinal edema of macula edema can ensue from of a breakdown of the blood retina barrier mediated in part by vascular endothelial growth factor (VEGF), a 45 kD glycoprotein. It is known that VEGF can increase vascular permeability; possibly by increasing phosphorylation of tight junction proteins such as occludin and zonula occluden. Similarly, in human nonocular disease states such as ascites, VEGF has been characterized as a potent vascular permeability factor (VPF).
Biochemically, VEGF is known to be a major contributor to the increase in the number of capillaries in tissue undergoing angiogenesis. Bovine capillary endothelial cells will proliferate and show signs of tube structures in vitro upon stimulation by VEGF. Upregulation of VEGF is a major component of the physiological response to exercise and its role in angiogenesis is suspected to be a possible treatment in vascular injuries.
VEGF causes an intracellular signaling cascade in endothelial cells. VEGF binding to VEGF receptor-2 (VEGFR-2) initiates a tyrosine kinase signaling cascade that stimulates the production of factors that variously stimulate vessel permeability (epithelial nitric oxide synthase; (eNOS), proliferation/survival (bFGF; basic fibroblast growth factor), migration (intercellular adhesion molecules (ICAMs); vascular cell adhesion molecules (VCAMs); matrix metalloproteases (MMPs)) and finally differentiation into mature blood vessels. As part of the angiogenic signaling cascade, NO (nitric oxide) is widely considered to be a major contributor to the angiogenic response because inhibition of NO significantly reduces the effects of angiogenic growth factors.
The normal human retina contains little or no VEGF; however, hypoxia causes upregulation of VEGF production. Disease states characterized by hypoxia-induced VEGF upregulation include, without limitation, CRVO and SRVO. This hypoxia induced upregulation of VEGF can be inhibited pharmacologically. Pe'er J. et al., Vascular Endothelial Growth Factor Upregulation In Human Central Retinal Vein Occlusion, OPHTHALMOLOGY 1998; 105:412-416. It has been demonstrated that anti-VEGF antibodies can inhibit VEGF driven capillary endothelial cell proliferation. Thus, attenuation of the effects of VEGF introduces a rationale for treatment of macular edema from venous occlusive disease.
Additionally, over expression of VEGF causes increased permeability in blood vessels in addition to stimulating angiogenesis. In “wet” or exudative macular degeneration, VEGF causes proliferation of capillaries into the retina. Since the increase in angiogenesis also causes edema, blood and other retinal fluids leak into the retina causing loss of vision. Our invention includes a novel treatment for macular degeneration without neovascularization by use of an anti-neovascular agent, such as a VEGF inhibiting aptamer, or other VEGF-inhibiting compound, such as a to stop the main signaling cascade for angiogenesis, thereby preventing these symptoms.
Diabetic retinopathy is the leading cause of blindness among adults aged 20 to 74 years. Macular ischemia is a major cause of irreversible vision acuity loss and decreased contrast sensitivity in patients with diabetic retinopathy. The capillary nonperfusion and decreased capillary blood flow that is responsible for this ischemia is seen clinically on the fluorescein angiogram as an increase in the foveal avascular zone (FAZ) or an irregularity of the outline of the FAZ. These findings are predictors of the other, perhaps more well-known, sight-threatening complications of diabetic retinopathy, including macular edema and proliferative retinopathy. Perhaps more importantly, extensive capillary nonperfusion is also a predictor of a poor visual prognosis from diabetic retinopathy.
There are treatments available or in development for macular edema and proliferative retinopathy, such as laser photocoagulation, intravitreal corticosteroids and anti-VEGF therapies. Although laser photocoagulation has been studied for vision loss directly associated with macular ischemia, there is currently no known treatment for this indication.
The exterior surface of the normal globe mammalian eye has a layer of tissue known as conjunctival epithelium, under which is a layer of tissue called Tenon's fascia (also called conjunctival stroma). The extent of the Tenon's fascia extending backwards across the globe forms a fascial sheath known as Tenon's capsule. Under Tenon's fascia is the episclera. Collectively, the conjunctival epithelium and the Tenon's fascia is referred to as the conjunctiva. As noted, under Tenon's fascia is the episclera, underneath which lies the sclera, followed by the choroid. Most of the lymphatic vessels and their associated drainage system, which is very efficient at removing therapeutic agents placed in their vicinity, is present in the conjunctiva of the eye.
A therapeutic agent can be administered to the eye to treat an ocular condition. For example the target tissue for an antihypertensive therapeutic agent to treat the elevated intraocular pressure characteristic of glaucoma can be the ciliary body 30 and/or the trabecular meshwork. Unfortunately, administration of an ocular topical antihypertensive pharmaceutical in the form of eye drops can result in a rapid wash out of most if not all of the therapeutic agent before it reaches the ciliary body and/or the trabecular meshwork target tissue, thereby requiring frequent redosing to effectively treat a hypertensive condition. Additionally, side effects to patients from topical administration of antiglaucoma medications and their preservatives range from ocular discomfort to sight-threatening alterations of the ocular surface, including conjunctival hyperemia (eye redness), stinging, pain, decreased tear production and function, decreased tear film stability, superficial punctate keratitis, squamous cell metaplasia, and changes in cell morphology. These adverse effects of topical antiglaucoma eyedrops can interfere with the treatment of glaucoma by discouraging patient dosing compliance, and as well long-term treatment with eyedrops is associated with a higher failure of filtration surgery. Asbell P. A., et al Effects of topical antiglaucoma medications on the ocular surface, Ocul Surf 2005 January;3(1):27-40; Mueller M., et al. Tear film break up time and Schirmer test after different antiglaucomatous medications, Invest Ophthalmol Vis Sci 2000 Mar. 15;41 (4):5283.
It is known to administer a drug depot to the posterior (i.e. near the macula) sub-Tenon space. See eg column 4 of U.S. Pat. No. 6,413,245. Additionally, it is known to administer a polylactic implant to the sub-tenon space or to a suprachoroidal location. See eg published U.S. Pat. No. 5,264,188 and published U.S. patent application 20050244463
An anti-neovascular agent can be used for the treatment of an ocular condition, such as a posterior ocular condition, which involves angiogenesis such as choroidal neovascularization (“CNV”). Delivery to the eye of a therapeutic amount of an anti-neovascula agent (a drug) can be difficult, if not impossible, for drugs with short plasma half-lives since the exposure of the drug to intraocular tissues is limited. Therefore, a more efficient way of delivering a drug to treat a posterior ocular condition, such as CNV, is to place the drug directly in the eye, such as directly into the vitreous. Maurice, D. M. (1983) Micropharmaceutics of the eye, Ocular Inflammation Ther. 1:97-102; Lee, V. H. L. et al. (1989), Drug delivery to the posterior segment” Chapter 25 In Retina. T. E. Ogden and A. P. Schachat eds., St. Louis: C V Mosby, Vol. 1, pp. 483-98; and Olsen, T. W. et al. (1995), Human scleral permeability: effects of age, cryotherapy, transscleral diode laser, and surgical thinning, Invest. Ophthalmol. Vis. Sci. 36:1893-1903.
Techniques such as intravitreal injection of a drug have shown promising results, but due to the short intraocular half-life of active agent, including anti-neovascular agents, intravitreal injections must be frequently repeated to maintain a therapeutic drug level. In turn, this repetitive process increases the potential for side effects such as infection, retinal detachment, endophthalmitis, and cataract.
An intraocular drug delivery system can be made of a biodegradable polymer such as a poly(lactide) (PLA) polymers, poly(lactide-co-glycolide) (PLGA) polymers, as well as copolymers of PLA and PLGA polymers. PLA and PLGA polymers degrade by hydrolysis, and the degradation products, lactic acid and glycolic acid, are metabolized into carbon dioxide and water.
Drug delivery systems have been formulated with various active agents. For example, it is known to make 2-methoxyestradiol poly lactic acid polymer implants (as rods and wafers), intended for intraocular use, by a melt extrusion method. See eg published U.S. patent application 20050244471. Additionally, it is known to make brimonidine poly lactic acid polymer implants and microspheres intended for intraocular use. See eg published U.S. patent applications 20050244463 and 20050244506, and U.S. patent application Ser. No. 11/395,019. Furthermore, it is known to make bimatoprost containing polylactic acid polymer implants and microspheres intended for intraocular use. See eg published U.S. patent applications 2005 0244464 and 2006 0182781, and U.S. patent applications Ser. Nos. 11/303,462, and; 11/371,118.
EP 488 401 discusses intraocular implants, made of certain polylactic acids, to be applied to the interior of the eye after a surgical operation for disorders of the retina/vitreous body or for glaucoma. EP 430539 discusses use of a bioerodible implant which is inserted in the suprachoroid.
U.S. application Ser. No. 11/565,917 filed Dec. 1,2006 discloses intraocular (including sub-tenon's) administration of various solid, drug-containing implants.
Intraocular drug delivery systems which are sutured or fixed in place are known. Suturing or other fixation means requires sensitive ocular tissues to be in contact with aspects of a drug delivery system which are not required in order to contain a therapeutic agent within or on the drug delivery system or to permit the therapeutic agent to be released in vivo. As such suturing or eye fixation means a merely peripheral or ancillary value and their use can increase healing time, patient discomfort and the risk of infection or other complications.
U.S. patent applications Ser. Nos. 11/742,350; 11/859,310; 11/952,938; 11/364,687 discuss use of intraocular compositions comprising anti-VEGF therapeutic agent, such as bevacizumab. Formulations of macromolecules for intraocular use are known, See eg applications Ser. Nos. 11/370,301; 11/364,687; 60/721,600; U.S. patent application Ser. No. 11/116,698 and 60/567,423.
Significantly, although dry AMO is the most common form of AMO, except for use of anti-oxidants (such as high dose vitamins C, E, beta carotene and/or zinc to neutralize reactive oxygen species in the retina) “there are no current therapies for the more common ‘dry’ AMO”. Gehrs K., et al., Age-related macular degeneration-emerging pathogenetic and therapeutic concepts, Ann Med 2006; 38: 450-471. Thus, “there is no effective treatment for the most prevalent atrophic (dry) form of AMO”. Petrukhin, K., New therapeutic targets in atrophic age-related macular degeneration, Expert Opin. Ther. Targets 92007) 11 (5): 625-639.
Thus it would be advantageous to have a sustained release drug delivery system suitable for intraocular use for treatment of dry AMD. What is needed therefore is a composition and method for treating dry AMD.